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https://www.readbyqxmd.com/read/27908751/enhanced-potency-of-bivalent-small-molecule-gp41-inhibitors
#1
Vladimir Sofiyev, Hardeep Kaur, Beth A Snyder, Priscilla A Hogan, Roger G Ptak, Peter Hwang, Miriam Gochin
Low molecular weight peptidomimetic inhibitors with hydrophobic pocket binding properties and moderate fusion inhibitory activity against HIV-1 gp41-mediated cell fusion were elaborated by increasing the available surface area for interacting with the heptad repeat-1 (HR1) coiled coil on gp41. Two types of modifications were tested: 1) increasing the overall hydrophobicity of the molecules with an extension that could interact in the HR1 groove, and 2) forming symmetrical dimers with two peptidomimetic motifs that could potentially interact simultaneously in two hydrophobic pockets on the HR1 trimer...
November 19, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27903803/the-human-cytomegalovirus-ie1-protein-antagonizes-pml-nuclear-body-mediated-intrinsic-immunity-via-the-inhibition-of-pml-de-novo-sumoylation
#2
Eva-Maria Schilling, Myriam Scherer, Nina Reuter, Johannes Schweininger, Yves A Muller, Thomas Stamminger
: PML nuclear bodies (NBs) are accumulations of cellular proteins embedded in a scaffold-like structure built by SUMO-modified PML/TRIM19. PML and other NB proteins act as cellular restriction factors against human cytomegalovirus (HCMV), however, this intrinsic defense is counteracted by the immediate-early protein 1 (IE1) of HCMV. IE1 directly interacts with the PML coiled-coil domain via its globular core region and disrupts NB foci by inducing a loss of PML SUMOylation. Here, we demonstrate that IE1 acts via abrogating the de novo SUMOylation of PML...
November 30, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27901467/structural-basis-for-the-disaggregase-activity-and-regulation-of-hsp104
#3
Alexander Heuck, Sonja Schitter-Sollner, Marcin Józef Suskiewicz, Robert Kurzbauer, Juliane Kley, Alexander Schleiffer, Pascaline Rombaut, Franz Herzog, Tim Clausen
The Hsp104 disaggregase is a two-ring ATPase machine that rescues various forms of non-native proteins including the highly resistant amyloid fibers. The structural-mechanistic underpinnings of how the recovery of toxic protein aggregates is promoted and how this potent unfolding activity is prevented from doing collateral damage to cellular proteins are not well understood. Here, we present structural and biochemical data revealing the organization of Hsp104 from Chaetomium thermophilum at 3.7 Å resolution...
November 30, 2016: ELife
https://www.readbyqxmd.com/read/27894878/functionally-conserved-rna-binding-and-protein-protein-interaction-properties-of-line-orf1p-in-an-ancient-clade-of-non-ltr-retrotransposons-of-entamoeba-histolytica
#4
Amit Kumar Gaurav, Jitender Kumar, Mridula Agrahari, Alok Bhattacharya, Vijay Pal Yadav, Sudha Bhattacharya
Retrotransposons are mobile genetic elements found in most organisms. Their origin and evolution is not very well understood. Retrotransposons that lack long terminal repeats (non-LTR) have been classified based on their reverse transcriptase (RT) and endonuclease sequences into groups, of which R2 is the most ancient. Its members contain a single open reading frame (ORF) while there are two ORFs in the other groups, of which ORF2 contains the RT and endonuclease sequences. It is thought that ORF1 was added later to the single-ORF-containing elements, and codes for a protein with nucleic acid binding activity...
November 25, 2016: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/27884598/coiled-coils-a-model-system-for-the-21st-century
#5
REVIEW
Andrei N Lupas, Jens Bassler
α-Helical coiled coils were described more than 60 years ago as simple, repetitive structures mediating oligomerization and mechanical stability. Over the past 20 years, however, they have emerged as one of the most diverse protein folds in nature, enabling many biological functions beyond mechanical rigidity, such as membrane fusion, signal transduction, and solute transport. Despite this great diversity, their structures can be described by parametric equations, making them uniquely suited for rational protein design...
November 21, 2016: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/27881300/structure-of-the-mind-complex-defines-a-regulatory-focus-for-yeast-kinetochore-assembly
#6
Yoana N Dimitrova, Simon Jenni, Roberto Valverde, Yadana Khin, Stephen C Harrison
Kinetochores connect centromeric nucleosomes with mitotic-spindle microtubules through conserved, cross-interacting protein subassemblies. In budding yeast, the heterotetrameric MIND complex (Mtw1, Nnf1, Nsl1, Dsn1), ortholog of the metazoan Mis12 complex, joins the centromere-proximal components, Mif2 and COMA, with the principal microtubule-binding component, the Ndc80 complex (Ndc80C). We report the crystal structure of Kluyveromyces lactis MIND and examine its partner interactions, to understand the connection from a centromeric nucleosome to a much larger microtubule...
November 3, 2016: Cell
https://www.readbyqxmd.com/read/27880913/mdia-and-rock-mediate-actin-dependent-presynaptic-remodeling-regulating-synaptic-efficacy-and-anxiety
#7
Yuichi Deguchi, Masaya Harada, Ryota Shinohara, Michael Lazarus, Yoan Cherasse, Yoshihiro Urade, Daisuke Yamada, Masayuki Sekiguchi, Dai Watanabe, Tomoyuki Furuyashiki, Shuh Narumiya
Here, we show neuronal inactivation-induced presynaptic remodeling and involvement of the mammalian homolog of Diaphanous (mDia) and Rho-associated coiled-coil-containing kinase (ROCK), Rho-regulated modulators of actin and myosin, in this process. We find that social isolation induces inactivation of nucleus accumbens (NAc) neurons associated with elevated anxiety-like behavior, and that mDia in NAc neurons is essential in this process. Upon inactivation of cultured neurons, mDia induces circumferential actin filaments around the edge of the synaptic cleft, which contract the presynaptic terminals in a ROCK-dependent manner...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27879387/rice-cellulose-synthasea8-plant-conserved-region-is-a-coiled-coil-at-the-catalytic-core-entrance
#8
Phillip S Rushton, Anna T Olek, Lee Makowski, John Badger, C Nicklaus Steussy, Nicholas C Carpita, Cynthia V Stauffacher
The crystallographic structure of a rice cellulose synthase, OsCesA8, plant conserved region (P-CR), one of two unique domains in the catalytic domain of plant CesAs, was solved to 2.4Å resolution. Two anti-parallel α-helices form a coiled-coil domain linked by a large extended connector loop containing a conserved trio of aromatic residues. The P-CR structure was fit into a molecular envelope for the P-CR domain derived from small-angle X-ray solution scattering data (SAXS). The P-CR structure and molecular envelope, combined with a homology-based chain trace of the CesA8 catalytic core, were modeled into a previously determined CesA8 SAXS molecular envelope to produce a detailed topological model of the CesA8 catalytic domain (CatD)...
November 22, 2016: Plant Physiology
https://www.readbyqxmd.com/read/27872140/primary-cilia-are-increased-in-number-and-demonstrate-structural-abnormalities-in-human-cancer
#9
Binnaz Yasar, Kim Linton, Christian Slater, Richard Byers
AIMS: Primary cilia play an important role in the regulation of cell signalling pathways and are thought to have a role in cancer but have seldom been studied in human cancer samples. METHODS: Primary cilia were visualised by dual immunofluorescence for anti-CROCC (ciliary rootlet coiled-coil) and anti-tubulin in a range of human cancers (including carcinomas of stomach, pancreas, prostate, lung and colon, lobular and ductal breast cancers and follicular lymphoma) and in matched normal tissue (stomach, pancreas, lung, large and small intestines, breast and reactive lymph nodes) samples using a tissue microarray; their frequency, association with proliferation, was measured by Ki-67 staining and their structure was analysed...
November 21, 2016: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/27870530/coiled-coil-mediated-activation-of-oligo-arginine-cell-penetrating-peptides
#10
Saskia Bode, Ilmar Kruis, Hans Adams, Wilbert Boelens, Ger Pruijn, Jan Van Hest, Dennis Lowik
A supramolecular approach was undertaken to create functionally activatable cell-penetrating peptides. Two tetra-arginines were assembled into an active cell-penetrating peptide by hetero-dimerizing leucine zippers. Three different leucine zipper pairs were evaluated of which the activation was found to be dependent on the association constant of the coiled-coil peptides. The weaker binding peptides required an additional disulfide linkage to educe cell-penetrating capacity, whereas for the most stable coiled-coil no additional stabilization was needed...
November 21, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27868170/protein-kinases-mechanisms-and-downstream-targets-in-inflammation-mediated-obesity-and-insulin-resistance
#11
REVIEW
Kalyana C Nandipati, Saravanan Subramanian, Devendra K Agrawal
Obesity-induced low-grade inflammation (metaflammation) impairs insulin receptor signaling. This has been implicated in the development of insulin resistance. Insulin signaling in the target tissues is mediated by stress kinases such as p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, inhibitor of NF-kB kinase complex β (IKKβ), AMP-activated protein kinase, protein kinase C, Rho-associated coiled-coil containing protein kinase, and RNA-activated protein kinase. Most of these kinases phosphorylate several key regulators in glucose homeostasis...
November 21, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27864379/foxn4-promotes-gene-expression-required-for-multiple-motile-cilia-formation
#12
Evan P Campell, Ian K Quigley, Chris Kintner
Multiciliated cell (MCC) differentiation involves extensive organelle biogenesis required to extend hundreds of motile cilia. Key transcriptional regulators have been identified that drive gene expression required for organelle biogenesis during MCC differentiation, which are activated by, and act downstream, of two related, small coiled-coil proteins, Multicilin and Gemc1. Here we identify foxn4 as a new downstream target of Multicilin required for MCC differentiation in the Xenopus skin. When Foxn4 activity is inhibited in Xenopus embryos, MCCs show transient ciliogenesis defects similar to those observed in mutants in Foxj1, a known key regulator of genes required for motile ciliation...
November 18, 2016: Development
https://www.readbyqxmd.com/read/27862842/the-wheat-nb-lrr-gene-tarcr1-is-required-for-host-defence-response-to-the-necrotrophic-fungal-pathogen-rhizoctonia-cerealis
#13
Xiuliang Zhu, Chungui Lu, Lipu Du, Xingguo Ye, Xin Liu, Anne Coules, Zengyan Zhang
The necrotrophic fungus Rhizoctonia cerealis is the major pathogen causing sharp eyespot disease in wheat (Triticum aestivum). Nucleotide binding-leucine rich repeat (NB-LRR) proteins often mediate plant disease resistance to biotrophic pathogens. Little is known about the role of NB-LRR genes involved in wheat response to R. cerealis. In this study, a wheat NB-LRR gene, named TaRCR1, was identified in response to R. cerealis infection using Artificial Neural Network analysis based on comparative transcriptomics and its defence role was characterized...
November 18, 2016: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/27859859/oligomerization-domains-in-the-glycan-binding-receptors-dc-sign-and-dc-signr-sequence-variation-and-stability-differences
#14
Ália Dos Santos, Andreas Hadjivasiliou, Felipe Ossa, Novandy K Lim, Aylin Turgut, Maureen E Taylor, Kurt Drickamer
Human dendritic cell-specific intercellular adhesion molecule-1 grabbing nonintegrin, DC-SIGN, and the sinusoidal endothelial cell receptor DC-SIGNR or L-SIGN, are closely related sugar-binding receptors. DC-SIGN acts both as a pathogen-binding endocytic receptor and as a cell adhesion molecule, while DC-SIGNR has only the pathogen-binding function. In addition to differences in the sugar-binding properties of the carbohydrate-recognition domains in the two receptors, there are sequence differences in the adjacent neck domains, which are coiled-coil tetramerization domains comprised largely of 23-amino acid repeat units...
November 17, 2016: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/27856304/a-heterozygous-dominant-negative-mutation-in-the-coiled-coil-domain-of-stat1-is-the-cause-of-autosomal-dominant-mendelian-susceptibility-to-mycobacterial-diseases
#15
Masahiro Ueki, Masafumi Yamada, Kenta Ito, Yusuke Tozawa, Saeko Morino, Yuho Horikoshi, Hidetoshi Takada, Shimaa Said Mohamed Ali Abdrabou, Shunichiro Takezaki, Ichiro Kobayashi, Tadashi Ariga
Heterozygous dominant-negative mutations of STAT1 are responsible for autosomal-dominant Mendelian susceptibility to mycobacterial diseases (AD-MSMD). So far, only 7 mutations have been previously described and are localized to 3 domains: the DNA-binding domain, the SH2 domain, and the tail segment. In this study, we demonstrated the first coiled-coil domain (CCD) mutation of c.749G>C, p.G250A (G250A) in STAT1 as a genetic cause of AD-MSMD in a patient with mycobacterial multiple osteomyelitis. This de novo heterozygous mutation was shown to have a dominant-negative effect on the gamma-activated sequence (GAS) transcriptional activity following IFN-γ stimulation, which could be attributable to the abolished phosphorylation of STAT1 from the wild-type (WT) allele...
November 14, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27856252/the-interchain-disulfide-cross-linking-of-tropomyosin-alters-its-regulatory-properties-and-interaction-with-actin-filament
#16
Alexander M Matyushenko, Natalia V Artemova, Daniil V Shchepkin, Galina V Kopylova, Salavat R Nabiev, Larisa V Nikitina, Dmitrii I Levitsky, Sergey Y Bershitsky
Tropomyosin (Tpm) is an α-helical coiled-coil actin-binding protein that plays a key role in the Ca(2+)-regulated contraction of striated muscles. Two chains of Tpm can be cross-linked by formation of a disulfide bond between Cys-190 residues. Normally, the SH-groups of these residues in cardiac muscle are in reduced state but in heart pathologies the interchain cross-linking of Tpm was shown to occur. Previous studies have shown that this cross-linking increases the thermal stability of the C-terminal part of the Tpm molecule...
November 14, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27853422/rock1-is-associated-with-alzheimer-s-disease-specific-plaques-as-well-as-enhances-autophagosome-formation-but-not-autophagic-a%C3%AE-clearance
#17
Yong-Bo Hu, Yang Zou, Yue Huang, Yong-Fang Zhang, Guinevere F Lourenco, Sheng-Di Chen, Glenda M Halliday, Gang Wang, Ru-Jing Ren
Alzheimer's disease (AD) is the most prevalent form of late-life dementia in the population, characterized by amyloid plaque formation and increased tau deposition, which is modulated by Rho-associated coiled-coil kinase 1 (ROCK1). In this study, we further analyze whether ROCK1 regulates the metabolism of amyloid precursor protein (APP). We show that ROCK1 is colocalized with mature amyloid-β (Aβ) plaques in patients with AD, in that ROCK1 enhances the amyloidogenic pathway, and that ROCK1 mediated autophagy enhances the intracellular buildup of Aβ in a cell model of AD (confirmed by increased ROCK1 and decreased Beclin 1 protein levels, with neuronal autophagosome accumulation in prefrontal cortex of AD APP/PS1 mouse model)...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27852792/fgfr-tacc-gene-fusions-in-human-glioma
#18
REVIEW
Anna Lasorella, Marc Sanson, Antonio Iavarone
Chromosomal translocations joining in-frame members of the fibroblast growth factor receptor-transforming acidic coiled-coil gene families (the FGFR-TACC gene fusions) were first discovered in human glioblastoma multiforme (GBM) and later in many other cancer types. Here, we review this rapidly expanding field of research and discuss the unique biological and clinical features conferred to isocitrate dehydrogenase wild-type glioma cells by FGFR-TACC fusions. FGFR-TACC fusions generate powerful oncogenes that combine growth-promoting effects with aneuploidy through the activation of as yet unclear intracellular signaling mechanisms...
November 16, 2016: Neuro-oncology
https://www.readbyqxmd.com/read/27851957/conserved-tetramer-junction-in-the-kinetochore-ndc80-complex
#19
Roberto Valverde, Jessica Ingram, Stephen C Harrison
The heterotetrameric Ndc80 complex establishes connectivity along the principal longitudinal axis of a kinetochore. Its two heterodimeric subcomplexes, each with a globular end and a coiled-coil shaft, connect end-to-end to create a ∼600 Å long rod spanning the gap from centromere-proximal structures to spindle microtubules. Neither subcomplex has a known function on its own, but the heterotetrameric organization and the characteristics of the junction are conserved from yeast to man. We have determined crystal structures of two shortened ("dwarf") Ndc80 complexes that contain the full tetramer junction and both globular ends...
November 15, 2016: Cell Reports
https://www.readbyqxmd.com/read/27851940/a-coiled-coil-peptide-shaping-lipid-bilayers-upon-fusion
#20
Martin Rabe, Christopher Aisenbrey, Kristyna Pluhackova, Vincent de Wert, Aimee L Boyle, Didjay F Bruggeman, Sonja A Kirsch, Rainer A Böckmann, Alexander Kros, Jan Raap, Burkhard Bechinger
A system based on two designed peptides, namely the cationic peptide K, (KIAALKE)3, and its complementary anionic counterpart called peptide E, (EIAALEK)3, has been used as a minimal model for membrane fusion, inspired by SNARE proteins. Although the fact that docking of separate vesicle populations via the formation of a dimeric E/K coiled-coil complex can be rationalized, the reasons for the peptides promoting fusion of vesicles cannot be fully explained. Therefore it is of significant interest to determine how the peptides aid in overcoming energetic barriers during lipid rearrangements leading to fusion...
November 15, 2016: Biophysical Journal
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